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Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans.

Abstract

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same region.

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  • Authors+Show Affiliations

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    Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, Strangeways Research Laboratory.

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    Division of Genetics and Epidemiology, The Institute of Cancer Research & Royal Marsden NHS Foundation Trust, London, UK.

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    Department of Urology, Norris Comprehensive Cancer Center, Keck School of Medicine, USC, Los Angeles, CA, USA, Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, USC, Los Angeles, CA, USA.

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    Medical College, Xiamen University, Xiamen, China.

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    Division of Genetics and Epidemiology, The Institute of Cancer Research & Royal Marsden NHS Foundation Trust, London, UK.

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    Division of Genetics and Epidemiology, The Institute of Cancer Research & Royal Marsden NHS Foundation Trust, London, UK.

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    Division of Genetics and Epidemiology, The Institute of Cancer Research & Royal Marsden NHS Foundation Trust, London, UK.

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    Division of Genetics and Epidemiology, The Institute of Cancer Research & Royal Marsden NHS Foundation Trust, London, UK.

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    Division of Genetics and Epidemiology, The Institute of Cancer Research & Royal Marsden NHS Foundation Trust, London, UK.

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    Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, Strangeways Research Laboratory.

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    Cancer Epidemiology Centre, The Cancer Council Victoria, Melbourne, VIC, Australia, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health.

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    Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, VIC, Australia.

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    Tissupath Pty Ltd., Melbourne, VIC, Australia.

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    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.

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    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.

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    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden, Department of Clinical Sciences, Danderyds Hospital, Stockholm, Sweden.

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    Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, USC, Los Angeles, CA, USA.

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    Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, USC, Los Angeles, CA, USA.

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    Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, USC, Los Angeles, CA, USA.

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    Department of Medical Biochemistry and Genetics Institute of Biomedicine, University of Turku, Turku, Finland, BioMediTech, University of Tampere and FimLab Laboratories, Tampere, Finland.

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    BioMediTech, University of Tampere and FimLab Laboratories, Tampere, Finland.

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    Department of Urology, Tampere University Hospital and Medical School, University of Tampere, Tampere, Finland.

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    Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

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    Cancer Epidemiology, Nuffield Department of Population Health.

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    Cancer Epidemiology, Nuffield Department of Population Health.

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    Department of Oncology, Addenbrooke's Hospital, Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK.

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    School of Social and Community Medicine, University of Bristol, Bristol, UK.

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    Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK, Faculty of Medical Science, John Radcliffe Hospital, University of Oxford, Oxford, UK.

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    Centre for Cancer Genetic Epidemiology, Department of Oncology, Strangeways Laboratory.

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    Centre for Cancer Genetic Epidemiology, Department of Oncology, Strangeways Laboratory, Department of Applied Health Research, University College London, London, UK.

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    Clinical Gerontology Unit, University of Cambridge, Cambridge, UK.

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    Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA, Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA.

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    Mayo Clinic, Rochester, MN, USA.

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    Mayo Clinic, Rochester, MN, USA.

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    Mayo Clinic, Rochester, MN, USA.

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    Department of Urology, University Hospital Ulm, Ulm, Germany.

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    Institute of Human Genetics, University of Ulm, Ulm, Germany.

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    Department of Urology, University Hospital Ulm, Ulm, Germany.

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    Department of Urology, Klinikum rechts der Isar der Technischen Universitaet Muenchen, Munich, Germany.

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    Division of Urologic Surgery, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Boston, USA.

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    International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.

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    International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.

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    International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.

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    Division of Genetic Epidemiology, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA, George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, UT, USA.

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    Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany, German Cancer Consortium (DKTK), Heidelberg, Germany.

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    Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany, German Cancer Consortium (DKTK), Heidelberg, Germany.

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    Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.

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    Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.

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    Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.

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    Biostatistics Program, Moffitt Cancer Center, Tampa, FL, USA.

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    Department of Urology and Alexandrovska University Hospital, Medical University, Sofia, Bulgaria.

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    Department of Medical Chemistry and Biochemistry, Molecular Medicine Center, Medical University, Sofia, Bulgaria.

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    Department of Medical Chemistry and Biochemistry, Molecular Medicine Center, Medical University, Sofia, Bulgaria.

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    Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation and School of Biomedical Science, Queensland University of Technology, Brisbane, Australia.

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    Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation and School of Biomedical Science, Queensland University of Technology, Brisbane, Australia.

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    Molecular Cancer Epidemiology Laboratory, Queensland Institute of Medical Research, Brisbane, Australia.

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    Department of Genetics, Portuguese Oncology Institute, Porto, Portugal, Biomedical Sciences Institute (ICBAS), University of Porto, Porto, Portugal.

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    Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.

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    Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.

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    The University of Surrey, Guildford, Surrey, UK.

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    The University of Surrey, Guildford, Surrey, UK.

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    The University of Surrey, Guildford, Surrey, UK.

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    Division of Genetics and Epidemiology, The Institute of Cancer Research & Royal Marsden NHS Foundation Trust, London, UK.

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    Division of Genetics and Epidemiology, The Institute of Cancer Research & Royal Marsden NHS Foundation Trust, London, UK.

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    Institute of Population Health, University of Manchester, Manchester, UK, Warwick Medical School, University of Warwick, Coventry, UK.

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    Institute of Population Health, University of Manchester, Manchester, UK, Warwick Medical School, University of Warwick, Coventry, UK.

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    Department of Twin Research & Genetic Epidemiology, King's College London, London, UK.

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    NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway, Department of Genetic Medicine and Development, University of Geneva, Switzerland and.

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    Dana Farber Cancer Institute, Boston, MA, USA.

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    Department of Urology, Norris Comprehensive Cancer Center, Keck School of Medicine, USC, Los Angeles, CA, USA, Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, USC, Los Angeles, CA, USA.

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    Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, Strangeways Research Laboratory.

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    Department of Urology, Norris Comprehensive Cancer Center, Keck School of Medicine, USC, Los Angeles, CA, USA, Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, USC, Los Angeles, CA, USA.

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    Division of Genetics and Epidemiology, The Institute of Cancer Research & Royal Marsden NHS Foundation Trust, London, UK.

    Division of Genetics and Epidemiology, The Institute of Cancer Research & Royal Marsden NHS Foundation Trust, London, UK, zsofia.kote-jarai@icr.ac.uk.

    Source

    Human molecular genetics 24:19 2015 Oct 01 pg 5589-602

    MeSH

    Chromosome Mapping
    European Continental Ancestry Group
    Genetic Predisposition to Disease
    Genome-Wide Association Study
    Genotype
    Humans
    Linkage Disequilibrium
    Male
    Polymorphism, Single Nucleotide
    Prostatic Neoplasms

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    26025378

    Citation

    Amin Al Olama, Ali, et al. "Multiple Novel Prostate Cancer Susceptibility Signals Identified By Fine-mapping of Known Risk Loci Among Europeans." Human Molecular Genetics, vol. 24, no. 19, 2015, pp. 5589-602.
    Amin Al Olama A, Dadaev T, Hazelett DJ, et al. Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans. Hum Mol Genet. 2015;24(19):5589-602.
    Amin Al Olama, A., Dadaev, T., Hazelett, D. J., Li, Q., Leongamornlert, D., Saunders, E. J., ... Kote-Jarai, Z. (2015). Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans. Human Molecular Genetics, 24(19), pp. 5589-602. doi:10.1093/hmg/ddv203.
    Amin Al Olama A, et al. Multiple Novel Prostate Cancer Susceptibility Signals Identified By Fine-mapping of Known Risk Loci Among Europeans. Hum Mol Genet. 2015 Oct 1;24(19):5589-602. PubMed PMID: 26025378.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans. AU - Amin Al Olama,Ali, AU - Dadaev,Tokhir, AU - Hazelett,Dennis J, AU - Li,Qiuyan, AU - Leongamornlert,Daniel, AU - Saunders,Edward J, AU - Stephens,Sarah, AU - Cieza-Borrella,Clara, AU - Whitmore,Ian, AU - Benlloch Garcia,Sara, AU - Giles,Graham G, AU - Southey,Melissa C, AU - Fitzgerald,Liesel, AU - Gronberg,Henrik, AU - Wiklund,Fredrik, AU - Aly,Markus, AU - Henderson,Brian E, AU - Schumacher,Fredrick, AU - Haiman,Christopher A, AU - Schleutker,Johanna, AU - Wahlfors,Tiina, AU - Tammela,Teuvo L, AU - Nordestgaard,Børge G, AU - Key,Tim J, AU - Travis,Ruth C, AU - Neal,David E, AU - Donovan,Jenny L, AU - Hamdy,Freddie C, AU - Pharoah,Paul, AU - Pashayan,Nora, AU - Khaw,Kay-Tee, AU - Stanford,Janet L, AU - Thibodeau,Stephen N, AU - Mcdonnell,Shannon K, AU - Schaid,Daniel J, AU - Maier,Christiane, AU - Vogel,Walther, AU - Luedeke,Manuel, AU - Herkommer,Kathleen, AU - Kibel,Adam S, AU - Cybulski,Cezary, AU - Wokołorczyk,Dominika, AU - Kluzniak,Wojciech, AU - Cannon-Albright,Lisa, AU - Brenner,Hermann, AU - Butterbach,Katja, AU - Arndt,Volker, AU - Park,Jong Y, AU - Sellers,Thomas, AU - Lin,Hui-Yi, AU - Slavov,Chavdar, AU - Kaneva,Radka, AU - Mitev,Vanio, AU - Batra,Jyotsna, AU - Clements,Judith A, AU - Spurdle,Amanda, AU - Teixeira,Manuel R, AU - Paulo,Paula, AU - Maia,Sofia, AU - Pandha,Hardev, AU - Michael,Agnieszka, AU - Kierzek,Andrzej, AU - Govindasami,Koveela, AU - Guy,Michelle, AU - Lophatonanon,Artitaya, AU - Muir,Kenneth, AU - Viñuela,Ana, AU - Brown,Andrew A, AU - ,, AU - ,, AU - ,, AU - ,, AU - ,, AU - Freedman,Mathew, AU - Conti,David V, AU - Easton,Douglas, AU - Coetzee,Gerhard A, AU - Eeles,Rosalind A, AU - Kote-Jarai,Zsofia, Y1 - 2015/05/29/ PY - 2015/03/19/received PY - 2015/05/27/accepted PY - 2015/5/31/entrez PY - 2015/5/31/pubmed PY - 2016/7/7/medline SP - 5589 EP - 602 JF - Human molecular genetics JO - Hum. Mol. Genet. VL - 24 IS - 19 N2 - Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same region. SN - 1460-2083 UR - https://www.unboundmedicine.com/medline/citation/26025378/Multiple_novel_prostate_cancer_susceptibility_signals_identified_by_fine_mapping_of_known_risk_loci_among_Europeans_ L2 - https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddv203 DB - PRIME DP - Unbound Medicine ER -